tbuckley/cabot-search huggingface dataset:
Comprehensive molecular phenotyping of<i>ARID1A</i>-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities
Authors: Chang Xu, Kie Kyon Huang, Jia Hao Law, Joy Shijia Chua, Taotao Sheng, Natasha M Flores, Melissa Pool Pizzi, Atsushi Okabe, Angie Lay Keng Tan, Feng Zhu, Vikrant Kumar, Xiaoyin Lu, Ana Morales Benitez, Benedict Shi Xiang Lian, Haoran Ma, Shamaine Wei Ting Ho, Kalpana Ramnarayanan, Chukwuemeka George Anene-Nzelu, Milad Razavi-Mohseni, Siti Aishah Binte Abdul Ghani, Su Ting Tay, Xuewen Ong, Ming Hui Lee, Yu Amanda Guo, Hassan Ashktorab, Duane Smoot, Shang Li, Anders Jacobsen Skanderup, Michael A Beer, Roger Sik Yin Foo, Joel Shi Hao Wong, Kaushal Sanghvi, Wei Peng Yong, Raghav Sundar, Atsushi Kaneda, Shyam Prabhakar, Pawel Karol Mazur, Jaffer A Ajani, Khay Guan Yeoh, Jimmy Bok-Yan So, Patrick Tan
Journal: Gut (2023)

Objective Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A -specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss. Design Genomic profiling of GC patients including a Singapore cohort (&gt;200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A -mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A -mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition. Results We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A -depletion caused loss of H3K27ac activation signals at ARID1A -occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2 . Promoter activation in ARID1A -mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A -genomic status. Conclusion Our results suggest a therapeutic strategy for ARID1A -mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.
Longitudinal analysis of persistent stress urinary incontinence after radical prostatectomy and time to definitive surgical treatment: Data from CaPSURE.
Authors: Avery Braun, Samuel L. Washington, Janet E. Cowan, Matthew R. Cooperberg, Peter Carroll
Journal: Journal of Clinical Oncology (2023)

347 Background: Persistent urinary incontinence (UI) after radical prostatectomy (RP) can have significant impact on quality of life, return to work and need for additional surgery. We aim to characterize the long-term cumulative incidence of incontinence procedure and report changes in urinary function (UF), urinary bother (UB), and work status from time of RP to 1 year postop. Methods: Participants treated by primary RP (1990-2020) for prostate cancer enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry of 43 US urologic practices. UI was defined as self-reported use of &gt;1 pad per day at 1 year after RP. UI procedure was tracked with CPT codes for urinary sling and artificial urinary sphincter (AUS). Participants reported work status (full-time paid, part-time paid, unpaid) and urinary scores (0-100) using UCLA Prostate Cancer Index. Associations of incontinence with changes in urinary scores (t-test) were assessed. Lifetable estimates and Cox proportional hazards regression were used to evaluate the risk of undergoing a UI surgical procedure, with model adjustment for pre-treatment age and urinary dysfunction, surgical characteristics, and post-surgical radiation. Results: Of 5742 men treated with primary RP, 641 (11%) reported UI as defined above at 1 year post-RP. Mean age was 61 years. A larger proportion of individuals with UI underwent open RP (93% vs 7%) and non-nerve sparing (62% vs 38%). At 1 year post RP, score decline in UF (-42.6 vs -11.7) and UB (-25.5 vs -2.7) were significantly worse in the incontinent group (all p&lt;0.01). Cumulative incidence of incontinence procedures was 1.4% at 10 years with median time to UI-redirected procedure of 36 months (IQR 12, 74) after RP. Incontinence procedures comprised 52.4% AUS, 15.8% sling, 6.3% both, and 25.4% unspecified. UI (HR 10.6,95%CI 6.3-17.9), older age (per decade, HR 2.0, 95% CI1.3-3.0), history of voiding dysfunction (HR 6.1,95% CI 2.9-12.8) and receipt of radiation (adjuvant or salvage) (HR 2.4, 95% CI1.2-4.8)) were associated with undergoing incontinence procedure. Conclusions: UI at 1 year after RP may occur in up to 11% of surgical recipients. However, the rate of intervention remained low with 1.4% of the total cohort undergoing an incontinence procedure within 10 years. Incontinence affected urinary quality of life. Median time to UI procedure was 36 months. This information suggests that a significant number of men may have long – term, untreated incontinence and even those who undergo procedures to manage it may not have it in a timely fashion.
FDG PET-CT imaging in assessing interim response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle invasive bladder cancer (MIBC): A prospective study.
Authors: Srikala S. Sridhar, Nicholas Power, Rodney H. Breau, Susanna Y. Cheng, Gregory Russell Pond, Peter W. M. Chung, Ur Metser, Mark Norman Levine, Som D. Mukherjee
Journal: Journal of Clinical Oncology (2023)

460 Background: Muscle invasive bladder cancer (MIBC) is an aggressive local disease where initial staging with conventional CT imaging is often suboptimal. To explore the role of PET-CT in both staging MIBC and assessing response to neoadjuvant chemotherapy (NAC), we conducted a prospective multicentre, randomized trial known as PETMUSE. We report here the first results from the neoadjuvant substudy which assessed interim PET-CT response after 2-3 cycles of NAC and how this correlated with disease free survival (DFS) and overall survival (OS). Methods: Patients with MIBC (T2a-4a, N0-3, M0) based on transurethral resection of their bladder tumor and CT staging were randomized 2:1 to PET-CT or no PET-CT. All PET-CT patients, receiving cisplatin-based NAC underwent a second PET-CT after 2 cycles of gemcitabine and cisplatin (GC) or 3 cycles of dose dense methotrexate, vinblastine, adriamycin, cisplatin (ddMVAC) to assess for interim response. Patients were scored (1-5) by 2 independent reviewers according to the extent of metabolic response on PET-CT. Disease-free survival (DFS) and overall survival (OS) were collected. Results: Between 2016 and 2021, 291 patients were enrolled on PETMUSE of which 46 participated in the neoadjuvant substudy. Median age was 68 (51-86); 36 (78%) were male; 26 were ECOG 0 (57%); 31 (68%) were T2, 13 (28%) were T3/T4; and 35 (76%) were node negative. In terms of NAC regimens: 22 (48%) received GC, 17 (37%) split dose GC, 6 (13%) ddMVAC, and 1 (2%) MVAC. On PET-CT, 23 (50%) had a complete metabolic response, 14 (30%) had a partial metabolic response, 5 (11%) had no change or mixed response and 4 (9%) had progressive disease or new lesion on PET scan. Metabolic response on PET-CT was a statistically significant prognostic factor for both DFS and OS (see Table). Conclusions: In MIBC patients receiving cisplatin-based NAC, metabolic response seen on interim PET-CT was correlated with DFS and OS. PET-CT warrants further study in this setting as a potential early indicator of response to NAC. Clinical trial information: NCT02462239 . [Table: see text][Table: see text]
A SEER-Medicare based quality score for patients with synchronous and metachronous metastatic upper tract urothelial carcinoma and its association with cost of care and survival.
Authors: Daniel D Joyce, Yong Shan, Courtney A. Stewart, Karim Chamie, Stephen A. Boorjian, Stephen B. Williams, Vidit Sharma
Journal: Journal of Clinical Oncology (2023)

482 Background: Population-based studies evaluating outcomes exclusively for metastatic upper tract urothelial carcinoma (mUTUC) are sparse and often only capture patients with de novo (synchronous) metastases as opposed to those who progress to metastatic disease (metachronous). We sought to evaluate the outcomes and costs associated with mUTUC and employ a novel methodology to identify both synchronous and metachronous mUTUC patients using claims data. Additionally, we created a guideline-based quality score to improve quality of care in this space. Methods: Using the SEER-Medicare database we identified patients aged 66 years and older diagnosed with mUTUC between 2004 and 2012. Achievement of the following quality criteria was assessed: 1) cancer-specific survival greater than 12 months; 2) receipt of systemic therapy; 3) receipt of hospice/palliative care. Kaplan-Meier survival curves and Cox proportional hazard models were used to compare overall survival between quality scores (0 vs. ≥1) and synchronous vs. metachronous mUTUC. Total healthcare and Medicare Part D out-of-pocket costs within two years of diagnosis were evaluated. Regression analyses were performed to assess characteristics associated with quality criteria and total healthcare costs. Results: Of the 1,223 patients identified, 381 (31.2%) and 842 (68.8%) had synchronous and metachronous mUTUC, respectively. At least one quality criterion was met in 40.2% of patients. Notably, only 54 patients (4.4%) received palliative care services. On multivariable analysis, patients with synchronous mUTUC (OR:0.55, 95%CI:0.41–0.72), and at least 3 comorbidities (OR:0.68, 95%CI:0.47–0.98), were less likely to achieve at least one quality criterion. Patients meeting quality criteria had longer survival compared with patients who did not meet criteria (HR:0.52, 95%CI: 0.46–0.59). Meeting at least one quality criterion was independently associated with increased costs ($94,677, 95%CI: 87702–101652 vs. $63575, 95%CI: 59598–67552) on multivariable regression analysis. Conclusions: Less than half of mUTUC patients met at least one quality criterion. Quality score achievement was associated with longer overall survival at a modest increase in total healthcare spending. These findings not only provide guidance for future study of rare diseases using secondary data, but also highlight inadequacies in the current management of mUTUC.
Impact of number of treatment lines following first-line (1L) immuno-oncology (IO) combination on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Audreylie Lemelin, Matthew Scott Ernst, Connor Wells, Vishal Navani, Bradley Alexander McGregor, Shirley S. Wong, Sumanta Monty Pal, Naveen S. Basappa, Anil Kapoor, Jae-Lyun Lee, Frede Donskov, Haoran Li, Takeshi Yuasa, Rose Chang, Lynn Huynh, Catherine Nguyen, Ashley Holub, Louise Clear, Mei Sheng Duh, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2023)

673 Background: Across the world, treatment of patients with mRCC is heterogeneous with different access to treatment sequences and number of lines of therapy (LOTs) employed. For instance, patients receiving first line (1L) nivolumab+ipilimumab (NIVO+IPI) may be offered second-line (2L) and third line (3L) vascular endothelial growth factor receptor targeted kinase inhibitor (VEGFR-TKI), whereas patients receiving 1L pembrolizumab or avelumab in combination with axitinib (IO+AXI) may only receive one subsequent VEGFR-TKI in 2L. We aimed to examine whether these different treatment strategies impact overall survival (OS). Methods: Adult mRCC patients who received at least three LOTs starting with 1L NIVO+IPI or at least two LOTs starting with 1L IO+AXI from the International Metastatic RCC Database Consortium (IMDC) centers were included. Kaplan-Meier analyses were used to estimate median OS (time from 1L to death). Results were stratified by 1L IMDC prognostic risk. Results: Among 128 patients who received at least three LOTs starting with 1L NIVO+IPI (median age 61 years, 77% White, 77% male, 37% from the US), 14% had favorable, 61% had intermediate, and 26% had poor IMDC risk. The most common 2L treatments following 1L NIVO+IPI were sunitinib (38%), cabozantinib (27%), and pazopanib (20%). Among 104 patients who received at least two LOTs starting with 1L IO+AXI (median age 62 years, 75% White, 67% male, 38% from the US), 28% had favorable, 48% had intermediate, and 25% had poor IMDC risk. The most common 2L treatments following 1L IO+AXI were cabozantinib (57%) and sunitinib (10%). Median OS are presented in the table, which suggested no difference in survival for patients who received at least two LOTs starting with 1L IO+AXI compared to patients who received at least three LOTs starting with 1L NIVO+IPI. Conclusions: Treatment for patients with mRCC varies depending on the 1L regimen chosen and by country. Our results demonstrate that, even with potential guaranteed time bias and IMDC imbalances, there is no statistically significant difference in OS for patients who received at least three LOTs starting with 1L NIVO+IPI and patients who received at least two LOTs starting with 1L IO+AXI, suggesting that selecting effective treatments in 1L resulting in fewer LOTs may have similar clinical outcomes as multiple LOTs. [Table: see text]
Urinary proteome as a prognostic factor in the deterioration of the quality of life of patients with localized prostate cancer during radiotherapy: Radiotoxicity Bladder Biomarkers (RABBIO) prospective trial.
Authors: Carole Helissey, Sophie Cavallero, Nathalie Guitard, Hélène Thery, Charles Parnot, Antoine Schernberg, Stanislas Mondot, Christos Christopoulos, Karim Malek, Emmanuelle Malaurie, Cyrus Chargari, Sabine Francois
Journal: Journal of Clinical Oncology (2023)

344 Background: Despite improvements in radiation techniques, pelvic radiotherapy is responsible for acute and delayed bladder adverse events, defined as radiation cystitis (CysR). About 50% of irradiated patients present acute symptoms and experience a significant decrease in their quality of life (QOL). The pathophysiology of CysR is not well understood, which limits our ability to study this process and develop treatments. The RABBIO study evaluates the correlation of urinary biomarkers with the intensity of acute CysR and the QOL of patients, assessed with the digital telemonitoring platform Cureety. Methods: Patients with intermediate-risk localized prostate cancer eligible for localized radiotherapy were included. Urinary biomarkers were analyzed before the start of radiotherapy, and at weeks (W) 4, 12 and 48 of irradiation. Between sample collection visits, patients completed various questionnaires related to radiation cystitis symptoms and QOL using a digital remote monitoring platform. Upon receipt of the questionnaires, an algorithm processed the information and classify patients according to the severity of symptoms and adverse events reported according to CTCAE. We also collected FACT-P questionnaires at baseline, W4 and W12. We correlated the levels of urinary biomarkers with the severity of acute CysR symptoms and patient-reported QOL. Results: The study started in March 2022, with 15 patients included to date. The median age was 76 (range 65-99). 80% (15/17) presented a localized prostate cancer de novo and 20% presented a biochemical recurrence. The compliance was 100% at baseline, 93% at W4 and 100% at W12. We collected a total of 172 AE questionnaires over the duration of the study so far, of which 61.0% (105/172) indicated a correct health status and 31.4% (54/172) a compromised status. The mean (range) FACT-P score at baseline for all patients was 33.9 (24 – 40), which changed to 29.8 (20 – 35) at W4, and 38.7 (37 – 42) at W12. Elevated SHBG (p=0.019, r=-0.93) and decreased IL8 (p=0.034, r=0.91) at baseline correlated with worse FACT-P score at W4. Conclusions: This prospective study is the first to explore the overexpression of inflammatory proteins in fluid biopsies from patients with symptoms of acute CysR. Our first results revealed that an elevated SHBG and a decreased IL8 in urine at baseline were a prognostic factor in the deterioration of QOL for localized prostate cancer patients during radiotherapy. The results of this study will allow us to develop strategies to limit radiation damage to the bladder and improve the QOL of patients. Clinical trial information: NCT05246774 .
Outcomes of partial nephrectomy for non-metastatic cT2 renal tumors: Results from a Canadian multi-institutional collaborative.
Authors: Rahul K. Bansal, Raees Cassim, Ryan Sun, Ranjeeta Mallick, Antonio Finelli, Simon Tanguay, Darrel E Drachenberg, Frederic Pouliot, Luke Lavallee, Alan I. So, Ricardo A. Rendon, Lori Wood, Anil Kapoor, Aly-Khan A. Lalani, Naveen S. Basappa, Bimal Bhindi, Lucas W. Dean, Georg A. Bjarnason, Rodney H. Breau
Journal: Journal of Clinical Oncology (2023)

690 Background: The role of partial nephrectomy (PN) is not well defined for cT2 renal cell carcinoma (RCC) as compared to radical nephrectomy (RN). The aim of this study was to examine oncological outcomes of PN as compared to RN for non-metastatic cT2 RCC. Methods: The Canadian Kidney Cancer information system was used to define patients who underwent surgery for non-metastatic cT2 RCC from January 2011 to October 2022. Patients with clear-cell, papillary, and chromophobe RCC were included. Other histology, multiple tumours, and hereditary RCC syndrome patients were excluded. Each PN patient was individually matched to RN up to 1:4 depending on availability of patients based on tumor size (+/- 1cm), histology, grade (clear cell and papillary), and necrosis (clear cell). Matched patients were analyzed as clusters. Results: A total of 1523 patients were identified, and 50 PN patients met study criteria who were then matched to 185 RN patients. Both groups had similar age, gender, smoking status, BMI, Charlson comorbidity index score, symptoms at presentation, baseline eGFR, hemoglobin and pathological characteristics. PN patients had smaller tumors (7.6 cm [IQR 2] vs 8.4 [IQR 2.4], p=0.05), had higher likelihood of undergoing open surgery (72.9% vs 31.8%, p&lt;0.0001) and less likely received adrenalectomy (2% vs 24.3%, p=0.0004). Positive surgical margin rates were similar in both groups (8.2% in PN vs 3.4% in RN, p=0.2). Median follow up was not significantly different in either group (3.6 yrs [IQR 4.7] in PN vs 3.3 [4.7] yrs in RN, p=0.9). During the follow up period, PN patients had higher risk of local recurrence (HR 3.0, 95%CI 1.08-8.37), lower risk of distant metastasis (HR 0.36, 95%CI 0.15-0.88), better cancer specific survival (HR 0.56, 95%CI 0.18-1.78) and overall survival (HR 0.36, 95%CI 0.11-1.19) and as compared to RN. At 6 months and beyond after surgery, PN patients had less decline in eGFR than RN patients (-16.6 [SD 21.1] vs -24.4[SD 16.2], p=0.0002). Complications rates between PN and RN were (18% vs 9%, p=0.057). Conclusions: In this multi-institutional Canadian cohort of patients with non-metastatic cT2 RCC undergoing surgery, PN compared to RN was associated with slightly higher risk of peri-operative complications, better preservation of renal function, and higher risk of local recurrence. The lower risk of distant metastasis and death was likely from residual confounding unaccounted for in the individual patient match. [Table: see text]
Real world (rw) racial differences in treatment (tx) patterns and clinical outcomes among patients (pts) with mCRPC.
Authors: Pedro C. Barata, Ella X. Du, Hongbo Yang, Chunyi Xu, Helen Guo, Caroline Cui, Jonathan Nazari, Alexander Niyazov
Journal: Journal of Clinical Oncology (2023)

95 Background: Contemporary rw data is needed to describe the heterogeneity of the tx landscape among diverse pt populations. This study assessed rw tx patterns and clinical outcomes among US pts receiving tx for mCRPC. Methods: Data from pts with mCRPC initiating first line (1L) tx between 2016 and 2019 were abstracted from medical charts. Clinical characteristics and tx patterns stratified by race (White [W], Black [B], and Other [O]) were compared using descriptive statistics. Rw progression-free survival (rwPFS) and overall survival (OS) were analyzed using Kaplan–Meier method. A multivariate Cox model explored associations between race and rwPFS/OS, controlling for confounders. Results: 122 physicians contributed data from 260 charts (W n=127, B n=81, O n=52 pts). The median age was 69 years; 64 (25%) had ECOG score ≥2. Common sites of metastases (mets) were bone (73%) and lymph nodes (34%); median Gleason score (GS) was 8.0, with no significant differences in sites of mets or GS among B and W pts. Most common txs prior to mCRPC included androgen deprivation therapy (ADT) monotherapy (39%), chemotherapy (CT; 15%), and novel hormonal therapy (NHT; 9%). Prior to mCRPC, more B pts were offered tx intensification with NHTs or CT compared with W pts (35% vs 14%). NHT was the most common 1L mCRPC therapy, followed by CT (Table). Compared with W pts, more B pts were offered NHT (65% vs 59%, P=0.44) and CT (26% vs 20%, P=0.38) in the 1L setting. Adjusted median rwPFS on 1L tx was 43.7 months (mo; 95% CI: 27–not estimable [NE]). A longer rwPFS was observed for B vs W pts; median rwPFS NE (95% CI: 34.7–NE) vs 34.7 mo (95% CI: 21.0–NE), hazard ratio (HR)=0.58 (95% CI: 0.35–0.97; P&lt;0.05). B pts had numerically greater OS vs W pts, HR=0.58 (95% CI: 0.31–1.1; P=0.09). Conclusions: In this rw study of pts receiving 1L tx for mCRPC, rwPFS was better compared with clinical trial data, particularly among B pts, who were more likely to receive life-prolonging txs in the 1L setting. These data suggest B pts might respond better to systemic therapies compared with W pts, and disparities observed in other settings may be attributed to access barriers. [Table: see text]